Several observational epidemiological studies indicate that anti- inflammatory treatments attenuate or prevent the symptoms of one of the most common mental disorders of late life, Alzheimer disease (AD). Neuropathological studies also support inflammatory or immune mechanisms in AD, including findings of reactive microglia within or near AD lesions. Such evidence, however, is circumstantial, and controlled, randomized drug trials are needed to determine efficacy. The proposed project is designed to determine if the commonly used non-steroidal anti-inflammatory drug (NSAID), ibuprofen, is efficacious in delaying progression of cognitive symptoms in people with age-related cognitive losses who are at risk for developing AD. A total of 135 subjects with age-associated memory impairment (AAMI) who are at risk for further cognitive decline (age 65 to 90 years, low scores on tests of verbal and visual memory and verbal fluency) will be randomized (double-blind design) to one of two treatment groups: ibuprofen (1200 mg/d) or placebo, and followed for two years for evidence of further cognitive decline. All randomized subjects will receive magnetic resonance imaging (MRI) scans and selective genotyping (apolipoprotein E [APOE] and human leukocyte antigen [HLA) to explore how baseline brain morphology (e.g., deep white matter disease hippocampal asymmetry and atrophy) and genetic risk for AD onset (e.g., APOE-4, HLA- A2) influence decline rates and treatment outcome. Subjects receiving ibuprofen are expected to show less evidence of cognitive decline than those receiving placebo. The proposed project builds upon our group's prior work on early detection of AD using brain imaging, genetic risk, and neuropsychological assessments. This project also is a logical follow-up to recent observation studies of a promising early intervention and will represent one of the first controlled, anti-inflammatory treatment trials for persons at high risk for age-related cognitive decline and the eventual development of AD.